Mice lacking the chromodomain helicase DNA-binding 5 chromatin remodeler display autism-like characteristics.

Although autism spectrum disorders (ASDs) share a core set of nosological features, they exhibit substantial genetic heterogeneity. A parsimonious hypothesis posits that dysregulated epigenetic mechanisms represent common pathways in the etiology of ASDs. To investigate this hypothesis, we generated a novel mouse model resulting from brain-specific deletion of chromodomain helicase DNA-binding 5 (Chd5), a chromatin remodeling protein known to regulate neuronal differentiation and a member of a gene family strongly implicated in ASDs. RNA sequencing of Chd5-/- mouse forebrain tissue revealed a preponderance of changes in expression of genes important in cellular development and signaling, sociocommunicative behavior and ASDs. Pyramidal neurons cultured from Chd5-/- cortex displayed alterations in dendritic morphology. Paralleling ASD nosology, Chd5-/- mice exhibited abnormal sociocommunicative behavior and a strong preference for familiarity. Chd5-/- mice further showed deficits in responding to the distress of a conspecific, a mouse homolog of empathy. Thus, dysregulated chromatin remodeling produces a pattern of transcriptional, neuronal and behavioral effects consistent with the presentation of ASDs.

Animal models to improve our understanding and treatment of suicidal behavior.

Worldwide, suicide is a leading cause of death. Although a sizable proportion of deaths by suicide may be preventable, it is well documented that despite major governmental and international investments in research, education and clinical practice suicide rates have not diminished and are even increasing among several at-risk populations. Although nonhuman animals do not engage in suicidal behavior amenable to translational studies, we argue that animal model systems are necessary to investigate candidate endophenotypes of suicidal behavior and the neurobiology underlying these endophenotypes. Animal models are similarly a critical resource to help delineate treatment targets and pharmacological means to improve our ability to manage the risk of suicide. In particular, certain pathophysiological pathways to suicidal behavior, including stress and hypothalamic-pituitary-adrenal axis dysfunction, neurotransmitter system abnormalities, endocrine and neuroimmune changes, aggression, impulsivity and decision-making deficits, as well as the role of critical interactions between genetic and epigenetic factors, development and environmental risk factors can be modeled in laboratory animals. We broadly describe human biological findings, as well as protective effects of medications such as lithium, clozapine, and ketamine associated with modifying risk of engaging in suicidal behavior that are readily translatable to animal models. Endophenotypes of suicidal behavior, studied in animal models, are further useful for moving observed associations with harmful environmental factors (for example, childhood adversity, mechanical trauma aeroallergens, pathogens, inflammation triggers) from association to causation, and developing preventative strategies. Further study in animals will contribute to a more informed, comprehensive, accelerated and ultimately impactful suicide research portfolio.

The neuroscience of suicidal behaviors: what can we expect from endophenotype strategies?

Vulnerability to suicidal behavior (SB) is likely mediated by an underlying genetic predisposition interacting with environmental and probable epigenetic factors throughout the lifespan to modify the function of neuronal circuits, thus rendering an individual more likely to engage in a suicidal act. Improving our understanding of the neuroscience underlying SBs, both attempts and completions, at all developmental stages is crucial for more effective preventive treatments and for better identification of vulnerable individuals. Recent studies have characterized SB using an endophenotype strategy, which aims to identify quantitative measures that reflect genetically influenced stable changes in brain function. In addition to aiding in the functional characterization of susceptibility genes, endophenotypic research strategies may have a wider impact in determining vulnerability to SB, as well as the translation of human findings to animal models, and vice versa. Endophenotypes associated with vulnerability to SB include impulsive/aggressive personality traits and disadvantageous decision making. Deficits in realistic risk evaluation represent key processes in vulnerability to SB. Serotonin dysfunction, indicated by neuroendocrine responses and neuroimaging, is also strongly implicated as a potential endophenotype and is linked with impulsive aggression and disadvantageous decision making. Specific endophenotypes may represent heritable markers for the identification of vulnerable patients and may be relevant targets for successful suicide prevention and treatments.

Correlates of hallucinations in schizophrenia: A cross-cultural evaluation.

INTRODUCTION: Demographic, clinical and familial factors may plausibly influence the manifestation of hallucinations. It is unclear if the pattern of the effects is similar in different environmental/cultural settings. AIMS: To evaluate factors associated with hallucination from a demographic, clinical and familial perspective in two distinct cultural settings. METHODS: Patients with a clinical diagnosis of schizophrenia (SZ) or schizoaffective disorder (SZA) were diagnosed systematically using DSM IV criteria. Two independent samples were recruited in India and USA using identical inclusion/exclusion criteria and assessment procedures (n=1287 patients total; 807 Indian and 480 US participants). The association of key demographic and clinical factors with hallucinations of different modalities was examined. To evaluate the impact of familial factors, we separately analyzed correlations among affected sibling pairs (ASPs, n=136, Indian; n=77, US). RESULTS: The prevalence of different modalities of hallucinations differed in the Indian and US samples, though the rank order of frequency was similar. The pattern of associations between selected variables and the risk of hallucinations was different across cultures, except for some correlations with indices of severity. No significant concordance was observed among the ASPs after correcting for multiple comparisons. CONCLUSIONS: The factors associated with hallucinations vary across environments. Our results are consistent with a multi-factorial etiology of psychopathology, but re-direct attention to endophenotypic features in the causal chain that precede the symptoms themselves.

Psychiatric endophenotypes and the development of valid animal models.

Endophenotypes are quantifiable components in the genes-to-behaviors pathways, distinct from psychiatric symptoms, which make genetic and biological studies of etiologies for disease categories more manageable. The endophenotype concept has emerged as a strategic tool in neuropsychiatric research. This emergence is due to many factors, including the modest reproducibility of results from studies directed toward etiologies and appreciation for the complex relationships between genes and behavior. Disease heterogeneity is often guaranteed, rather than simplified, through the current diagnostic system; inherent benefits of endophenotypes include more specific disease concepts and process definitions. Endophenotypes can be neurophysiological, biochemical, endocrine, neuroanatomical, cognitive or neuropsychological. Heritability and stability (state independence) represent key components of any useful endophenotype. Importantly, they characterize an approach that reduces the complexity of symptoms and multifaceted behaviors, resulting in units of analysis that are more amenable to being modeled in animals. We discuss the benefits of more direct interpretation of clinical endophenotypes by basic behavioral scientists. With the advent of important findings regarding the genes that predispose to psychiatric illness, we are at an important crossroads where, without anthropomorphizing, animal models may provide homologous components of psychiatric illness, rather than simply equating to similar (loosely analogized) behaviors, validators of the efficacy of current medications or models of symptoms. We conclude that there exists a need for increased collaboration between clinicians and basic scientists, the result of which should be to improve diagnosis, classification and treatment on one end and to increase the construct relevance of model organisms on the other.

Family and twin strategies as a head start in defining prodromes and endophenotypes for hypothetical early-interventions in schizophrenia.

In an effort to share the experiences of 'genotype-hunters'-who have approached the difficult task of forecasting future schizophrenia in the young offspring or other relatives of index cases, in new samples guided by the prior probabilities of 15% in offspring or 50% in identical co-twins-with 'early-interventionists'-who focus on purported prodromal symptoms in children who would be treated pharmacologically to prevent the development of schizophrenia-we provide a focused review that emphasizes the hazards of false positives in both approaches. Despite the advantages prospective high-risk strategies have had from clinical and laboratory findings that implicate some prodromal signs and endophenotypes, e.g. attention, memory, and information processing evaluations, the yields are not sufficient for practical applications involving antipsychotic drugs for undiagnosed children. Even more caution than usual is required, given the suggestions that the developing neocortex is vulnerable to dopaminergic exposure.

A new MMPI-derived indicator of liability to develop schizophrenia: evidence from the New York High-Risk Project.

A large body of research indicates that the liability to develop schizophrenia is largely genetically mediated, although phenotypic expression requires environmental triggers/insults and/or epigenetic and/or stochastic factors. In an effort to identify the precise environmental factors that precipitate a predisposition to schizophrenia, researchers have implemented a high-risk model-the prospective study of offspring born to schizophrenic parents. As it is difficult to ascertain exactly which of the "high-risk" participants will actually develop the disorder, we examined the validity of an experimental MMPI scale, Schizophrenia Proneness (SzP), and the Moldin-Gottesman psychometric index to identify such individuals. Results suggest that the SzP scale can be an effective predictor of schizophrenia-related psychoses. A revised psychometric index is offered for further study.

No association between dopamine D2 receptor gene (DRD2) and human intelligence.

Significantly diminished intellectual functioning, as indicated by appropriately administered IQ tests with scores below 70, is a frequent mental handicap leading to severe social disadvantages and serves as a paradigm for molecular genetic research of complex disorders and traits due to its multitude of known and unknown, genetic as well as environmental causes. Since the number of confounding variables is expected to be considerably reduced in the normal population at the opposite ends of the IQ distribution, we employed a contrast of extremes approach by comparing adults of high (N = 71) and average IQ (N = 78) in association studies to search for genes involved in the multigenic forms of familial mental retardation. The dopamine D2 receptor gene (DRD2) was chosen as a candidate gene for general cognitive ability (g) since it has been found to be associated with visuospatial ability which in turn is highly correlated with g. Confirming two similar studies in children, however, no significant differences were obtained. Given three negative studies, the DRD2 gene is unlikely to pay a major role in g.

Psychopathology through a life span-genetic prism.

The variation observed in individual differences for normal and psychopathological behaviors has genetic factors as a major contributor at the most distal end of a complex gene-to-behavior pathway. Research into the etiologies of such major mental diseases as schizophrenia is facilitated by adopting the approach used for complex adaptive systems as pursued by those who study coronary artery disease and diabetes. Putative risk factors for developing the liabilities to the major disorders can be inferred from population genetic strategies using twins, families, and adoptees. Weights to indicate the relative importance of such risk factors require a perspective from the use of effect sizes and odds ratios so as to make the most efficient use of scarce resources. The challenge to the field of psychology is to join in with cross-disciplinary ventures and to adapt to rapid changes with innovations in research strategies.

Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: the New York High-Risk Project.

OBJECTIVE: Childhood neurobehavioral deficits in offspring of schizophrenic, affectively ill, and psychiatrically normal parents were evaluated as predictors of schizophrenia-related psychoses in adulthood. METHOD: The offspring were tested with neurobehavioral measures at 7-12 years of age and assessed in mid-adulthood for axis I diagnoses. The relationships of childhood deficits in attention, verbal memory, and gross motor skills to adulthood schizophrenia-related psychoses were examined in separate path analyses by using logistic regression equations. Sensitivity and specificity were determined for each of the childhood dysfunctions. RESULTS: For the offspring of schizophrenic parents, childhood deficits in verbal memory, gross motor skills, and attention identified 83%, 75%, and 58%, respectively, of the subjects with schizophrenia-related psychoses; 50% were identified by all three variables combined. False positive rates in subjects who did not develop schizophrenia-related psychoses ranged from 18% for those with deficits in attention during childhood to 28% for those with deficits in memory. The three variables had low deficit rates in the offspring of the other two parental groups and were not associated with other psychiatric disorders in any group. CONCLUSIONS: Schizophrenia-related psychoses in adulthood are distinguished in subjects at risk for schizophrenia by childhood deficits in verbal memory, gross motor skills, and attention. The findings suggest that deficits in these variables are relatively specific to schizophrenia risk and may be indicators of the genetic liability to schizophrenia.

A twin study of communication disturbances in schizophrenia.

Relatives of schizophrenia patients have demonstrated several different types of subtle communication disturbances. This study used twin methodology to address the question of whether certain of these disturbances might be reflective of genetic vulnerability. Verbatim interviews from a sample of monozygotic and dizygotic twins in which at least one member of each twin pair had a diagnosis of schizophrenia were rated for three different types of referential communication disturbances. Monozygotic versus dizygotic nonschizophrenic co-twins were compared on each type of disturbance. Associations between the language variables and object sorting test performance also were examined. Differences among subjects in levels of global psychopathology were controlled. Schizophrenic participants showed higher levels of communication disturbance than nonschizophrenic co-twins. One type of communication failure, the "missing information" reference, discriminated monozygotic from dizygotic nonschizophrenic co-twins. This type of failure was associated with specific types of errors on the object sorting test. These findings suggest that missing information references may be an expression of schizophrenia-related genetic vulnerability.

Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics.

Twin studies have been vital for establishing an important genetic contribution to the etiology of schizophrenia. The five newest studies since 1995 from Europe and Japan have confirmed earlier findings. They yielded probandwise concordance rates of 41-65% in monozygotic (MZ) pairs and 0-28% in dizygotic (DZ) pairs, and heritability estimates of approximately 80-85%. Twin studies are also valuable for investigating the etiological relationships between schizophrenia and other disorders, and the genetic basis of clinical heterogeneity within schizophrenia. Studies of discordant MZ pairs provide further insights into non-inherited factors that contribute to the multifactorial etiology of this disorder. More recently, twin studies have begun to be used to directly investigate molecular genetic and epigenetic processes underlying schizophrenia.

Heritability of MMPI Harris-Lingoes and Subtle-Obvious subscales in twins reared apart.

A large sample of identical and fraternal twins who had been reared apart was used to examine the genetic and environmental architecture of the MMPI Subtle-Obvious and Harris-Lingoes subscales. Univariate genetic analyses indicated significant heritability for all 28 of the Harris-Lingoes subscales (estimates ranged from.23 to.61), all five Obvious subscales (estimates ranged from.37 to.56) and four of the five Subtle subscales (estimates ranged from.27 to.35). Two randomly constructed scales were analyzed as controls; neither of these scales showed significant heritability. Exploratory correlational findings suggested that three of the Wiener-Harmon Subtle subscales may tap aspects of psychological health, naivete, or repression. Ma-S may come closest to Wiener and Harmon s intent. Although they apparently diverge from their original purpose, it may be too early to abandon the low face valid items of the Subtle subscales.

EEG differences in monozygotic twins discordant and concordant for schizophrenia.

In an electroencephalographic (EEG) study of 27 pairs of monozygotic (MZ) twins discordant for schizophrenia, 13 pairs of MZ twins concordant for schizophrenia, 40 pairs of healthy MZ twins, and 91 healthy, unrelated subjects with repeated assessments, we investigated (a) the trait quality of brainwave patterns with respect to interindividual differences, intraindividual stability over time, and within-pair MZ concordance; (b) the EEG characteristics that enable discrimination between affected and unaffected individuals; and (c) the EEG characteristics that reflect the severity of illness. In comparison with healthy control subjects, the MZ twins who were discordant and concordant for schizophrenia exhibited a much lower within-pair EEG concordance, so that EEG abnormalities associated with schizophrenia and manifested differently in the co-twins concordant for schizophrenia seemed to reflect nongenetic, pathological developments of genetically identical brains.

Heritability estimates for psychotic disorders: the Maudsley twin psychosis series.

BACKGROUND: Previous twin studies have supported a genetic contribution to the major categories of psychotic disorders, but few of these have employed operational diagnostic criteria, and no such study has been based on a sample that included the full range of functional psychotic disorders. METHODS: A total of 224 twin probands (106 monozygotic, 118 dizygotic) with a same-sex co-twin and a lifetime history of psychosis was ascertained from the service-based Maudsley Twin Register in London, England. Research Diagnostic Criteria psychotic diagnoses were made on a lifetime-ever basis. Main-lifetime diagnoses of DSM-III-R and International Statistical Classification of Diseases, 10th Revision schizophrenia were also made. Probandwise concordance rates and correlations in liability were calculated, and biometrical model fitting applied. RESULTS: A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear. Heritability estimates for Research Diagnostic Criteria schizophrenia, schizoaffective disorder, mania, DSM-III-R schizophrenia, and International Statistical Classification of Diseases, 10th Revision schizophrenia were all between 82% and 85%. None of the estimates differed significantly from any other. CONCLUSIONS: Heritability estimates for schizophrenia, schizoaffective disorder, and mania were substantial and similar. Population morbid risk estimates were inferred rather than directly measured, but the results were very similar to those from studies where morbid risks were directly estimated.